Indian Journal of Pathology and Microbiology

ORIGINAL ARTICLE
Year
: 2010  |  Volume : 53  |  Issue : 4  |  Page : 750--756

Sarcomatoid carcinoma of the upper aerodigestive tract: An immunohistochemical analysis demonstrating latent Epstein-Barr virus in a subset of eight cases


Demet Etit1, Deniz Altinel2, Umit Bayol2, Ayca Tan2, Suheyla Cumurcu2,  
1 Department of Pathology, Tepecik Research and Training Hospital, Izmir;Department of Pathology, Ataturk Research and Training Hospital, Izmir, Turkey
2 Department of Pathology, Tepecik Research and Training Hospital, Izmir, Turkey

Correspondence Address:
Demet Etit
Department of Pathology, Tepecik Research and Training Hospital, Izmir
Turkey

Abstract

Background: Sarcomatoid or spindle cell carcinomas are rare malignancies which are considered as a poorly differentiated variant of squamous cell carcinoma. Epstein-Barr virus (EBV) is associated with a wide variety of malignancies. Materials and Methods: We examined the expression of EBV latent membrane protein-1 (LMP-1) and EBV EBNA-2 as well as the immunohistochemical profile of AE-1/AE-3, vimentin, desmin, CK 5-6, smooth muscle actin (SMA), p63, S-100, p53 and CD-117 with the clinicopathological correlation of eight patients of sarcomatoid carcinoma (SC) in the upper aerodigestive tract. Results: Four cases showed EBV LMP-1 positivity (50%) and there was no EBV EBNA-2 positivity. However, the EBV LMP-1 results of our series could be considered only as a coincidental finding in the SCs of the upper aerodigestive tract. Conclusions: This finding supports the idea that further studies based on larger series might be helpful enlighting the role played by EBV in carcinogenesis of SC.



How to cite this article:
Etit D, Altinel D, Bayol U, Tan A, Cumurcu S. Sarcomatoid carcinoma of the upper aerodigestive tract: An immunohistochemical analysis demonstrating latent Epstein-Barr virus in a subset of eight cases.Indian J Pathol Microbiol 2010;53:750-756


How to cite this URL:
Etit D, Altinel D, Bayol U, Tan A, Cumurcu S. Sarcomatoid carcinoma of the upper aerodigestive tract: An immunohistochemical analysis demonstrating latent Epstein-Barr virus in a subset of eight cases. Indian J Pathol Microbiol [serial online] 2010 [cited 2021 Jul 30 ];53:750-756
Available from: https://www.ijpmonline.org/text.asp?2010/53/4/750/70969


Full Text

 Introduction



Sarcomatoid or spindle cell carcinomas are rare malignancies which are considered as a poorly differentiated variant of squamous cell carcinoma composed of neoplastic cells that have a mesenchymal or sarcomatoid phenotype. [1],[2] These tumors are not uncommonly challenging in classification, diagnosis, and treatment. [3],[4],[5],[6],[7],[8] According to the World Health Organization's working group definition, sarcomatoid carcinoma (SC) is a biphasic tumor composed of a SCC, either in the form of in situ or invasive carcinoma, and a malignant spindle component with a mesenchymal appearance but of epithelial origin. [9] While some cases may have obvious epithelial areas, the sarcomatoid component is almost indistinguishable from a true sarcoma. [10] When the malignant surface epithelium is histologically obvious, the diagnosis of a SC is made confidently. However, when the surface epithelium is ulcerated, the diagnosis becomes more difficult. The "epithelial" differentiation of the spindle cell component has only been proposed in mainly single case reports. [3],[7],[10],[11],[12],[13],[14]

Epstein-Barr virus (EBV) causes infectious mononucleosis and is also associated with a wide variety of malignancies, affecting up to 1% of humans worldwide, and warrants increased focus on laboratory assays to detect and characterize the infection. Within a given neoplasm, consistent presence of EBV implies that the virus might contribute to pathogenesis or maintenance of the clonal process. [15] While EBV latent membrane protein-1 (LMP-1) has an oncogenic potential, upregulating the expression of Bcl-2, [16] the EBV EBNA-2 protein is a transcription factor that coordinates latent viral gene expression and induces several cellular genes that are important for proliferation. [17]

As it is well known, some neoplasms such as nasopharyngeal carcinoma and Burkitt's lymphoma are associated with EBV, while some neoplasms such as sinonasal undifferentiated carcinoma are typically non-associated with EBV. [18],[19],[20]

In order to study the role of EBV in the SCs of the upper aerodigestive tract, we examined the expression of EBV LMP-1 and EBV EBNA-2 as well as the immunohistochemical profile of AE-1/AE-3, vimentin, desmin, CK 5-6, smooth muscle actin (SMA), p63, S-100, p53 and CD-117 with the clinicopathological correlation of eight patients.

 Materials and Methods



Cases

From the authors' institutional and consultation files, the pathologic material, including the reports and routine formalin-fixed, paraffin-embedded, hematoxylin and eosin (H and E) stained sections of eight cases were reviewed. All cases for which the available tissues for immunohistochemical staining could be retrieved were histologically characterized as SC .

Patients' age, gender, tumor size and the macroscopic findings of the tumors were taken from the reports. Clinical findings of the cases and follow-up data were obtained through contact with the primary physicians or reviews of patients' medical records [Table 1].{Table 1}

Immunohistochemical Stains

Immunohistochemical stainings for EBV LMP-1, EBV EBNA-2, AE-1/AE-3, vimentin, desmin, CK 5-6, SMA, p63, S-100, p53 and CD-117 were performed on the 5-mm, formalin-fixed, paraffin-embedded sections and processed using automated immunostaining (Ventana Benchmark XT, code:E750-BMKXT-FS) [Table 2].{Table 2}

 Results



Clinical Findings

The patients consisted of seven men and one woman. Mean patient age was 63 years (range 42-75 years). Hoarseness was the most common complaint. The patients were neither immunocompromised nor HIV related.

While larynx was the most frequent site of involvement (7/8), in one case tumor was located at the base of the tongue.

Treatment in this group included total laryngectomy (1), partial laryngectomy (3) including cordectomy (1). Those four patients had neck dissection as a part of laryngectomy treatment and the lymph nodes were without metastases. In four patients, tumoral exicision either as an initial surgery or for a recurrent tumor was performed.

In the median follow-up for 15 months (range 2 months-2 years) of four available patients, there was no evidence of disease.

Pathologic Findings

All the tumors (8/8) exhibited a polypoid or exophytic growth pattern. The recorded tumor size in eight patients ranged from 0.3 to 15 cm (mean 3 cm). Seven were located in the larynx. Extensive surface ulceration was a typical feature. A diligent search was necessary to find a residual squamous epithelium. In all cases, squamous epithelial changes from hyperplasia to invasive conventional carcinoma were observed [Figure 1] and [Figure 2]. The spindle cell component was either resembling a pleomorphic sarcoma or showing relatively bland, fibrosarcoma-like appearence [Figure 3] and [Figure 4]. In two cases, focal necrosis was observed. In pleomorphic sarcoma-like cases, cells with spindle, polygonal cytoplasms and eosinophilic macronucleoli with hyperchromatic nuclei were noted, while fibrosarcoma-like cases had relatively bland cellular features. The mean number of mitosis was 11 in 10 HPF (range 2-37). In four cases, atypical mitoses were identified [Table 1].{Figure 1}{Figure 2}{Figure 3}{Figure 4}

The results of immunostaining are shown in [Table 3]. Overall, the spindle cell component showed positivity for at least one keratin marker in seven tumors (87%). While case 6 only showed CK5-6 positivity in the spindle component, case 7 demonstrated only p63 positivity as an epithelial marker. Staining for keratins often was focal. All the cases were stained with vimentin. SMA in two cases, desmin in one, S-100 in one and focal CD-117 positivity in three cases were noted. P53 positivity was variable from 1-5% to 80-90% [Figure 5], [Figure 6], [Figure 7].{Table 3}{Figure 5}{Figure 6}{Figure 7}

Out of eight cases, four (50%) showed diffuse and strong nuclear positivity for EBV LMP-1, while there was no EBV EBNA-2 positivity in the series. The staining was also seen in in situ carcinoma. There was no staining in inflamatory cells either within tumor or in the areas adjacent to the tumor. In the 10 control cases of conventional SCC of the larynx, EBV LMP-1 and EBV EBNA-2 were performed. None of them showed positivity either within the invasive or in the in situ carcinomas for those two markers. Interestingly, while there was no immunostaining with EBV LMP-1 in the initial specimen in case 1, the recurrent tumor which had more conventional squamous cell carcinoma areas showed diffuse and strong EBV LMP-1 positivity. This patient or any other patients of the series had no radiotherapy or any other immune deficiency history [Figure 8], [Figure 9],[Figure 10], [Figure 11].{Figure 8}{Figure 9}{Figure 10}{Figure 11}

 Discussion



SC of the upper aerodigestive tract is one of the difficult diagnostic challenges for surgical pathologists. Histogenesis has been settled in favor of a divergent (mesenchymal) differentiation of a carcinoma, most often a squamous cell carcinoma. Finding the carcinoma and/or its immunohistochemical marker in the metaplastic cells supports the correct diagnosis. Based on a review of all of the consultation cases of the Armed Forces Institute of Pathology of benign or malignant primary laryngeal neoplasms, laryngeal SC accounted for approximately 2.7%, a finding that shows slightly higher value than the results reported in the literature. Eight primary SCs were identified in our files in a total of 36,237 surgical pathology cases in a 4-year period.

There was a major predominancy of male-to-female ratio in the present study of 7:1, similar to that in the earlier reports. [12],[13],[21],[22],[23],[24],[25] SC usually develops in the seventh decade of life, with the mean age in this clinical series being 65.6 years. [10],[12],[13],[21],[22],[23],[24],[25],[26],[27]

Larynx is among the most common sites in the head and neck. Less frequently, it arises in the hypopharynx. [28],[29] In our study, the larynx was found to be the most common site.

Patients usually present with hoarseness, dysphagia and airway obstruction. [3],[10],[21],[22],[25],[30] In all the cases in the present study, the main complaint was hoarseness.

Most of the tumors recorded in the literature are polypoid, pedunculated, or exophytic in appearance. [2],[10],[12],[13],[21],[22],[23],[25],[26],[31],[32],[33] All the tumors in our series macroscopically showed polypoid or exophitic growth pattern with superficial epithelial ulceration.

The spindle cell component usually forms the bulk of the tumor, which can resemble a fibrosarcoma or malignant fibrous histiocytoma. Some cases can mimic a less malignant neoplasm or a reactive fibroblastic proliferation with or without stromal atypia. [3],[10],[29] Rhabdosarcomatous or osteosarcomatous differentiation may occur particularly in cases with previous radiotherapy history. In the current study, out of eight cases, while five resembled fibrosarcoma, three cases had a more pleomorphic malignant fibrous histiocytoma-like appearance. None of the patients had radiotherapy history. Evidence for squamous epithelial origin can be seen as either in situ carcinoma or as invasive SCC. Sometimes, SCC cannot be seen due to extensive ulceration. Occasionally, only spindle cells are seen. In our series, all the cases showed surface ulceration and all had squamous epithelial changes ranging from squamous dysplasia to invasive SCC.

The results of a variety of immunohistochemical studies have been reported. [4],[10],[14],[22],[31],[34] Among the epithelial markers, the most sensitive and reliable markers in S Cs appear to be keratin (AE1/AE3). Keratin positivity can be seen in spindle cells in 40-85%. [9] In all cases of the present study, while at least one epithelial antibody was positive in each tumor tested, six lesions showed both AE1/AE3 and p63 positivity.

A divergent mesenchymal differentiation of the tumor cells seems to be supported by the carcinoma cells acquiring the potential to express a mesenchymal phenotype at the light microscopic, immunohistochemical, and ultrastructural levels. [3],[4],[8],[10],[13],[14],[22],[26],[27],[31],[32],[35],[36],[37],[38],[39],[40] Spindle cells express vimentin and other mesenchymal filaments such as SMA, S-100 and desmin. [9] As would be expected, the intermediate filament vimentin showed strong immunoreaction in the sarcomatoid component in all patients in the series (100%), with 38% demonstrating reactivity with SMA, 12% with S-100 protein, and 10% each with desmin. In one study, c-kit (CD117) and other kinases in SCCs have shown significantly higher positivity than in benign samples. [41] In our study, CD117 was focally positive in three cases out of eight (38%). Immunostaining of p53 might serve as a potential adjunct in pathologic evaluation of head and neck tumors to predict the risk. [42] In our series, all cases (100%) had P53 immunoreactivity ranging from 5-10% to 80-90%.

Based upon serologic surveys, it can be said that more than 90% of adults worldwide have been infected by the EBV. [43] Nearly all the infections are acquired by oral contact with a person carrying EBV in saliva. [44] While EBV has been linked to various carcinomas such as gastric carcinoma; in the head and neck region, the best known example of this association is nasopharyngeal carcinoma. Recently, the studies on some other carcinomas related with EBV have been reported, such as in oral carcinogenesis and basaloid-squamous carcinoma of the nasopharynx. [45],[46] Some reports have pointed to EBV positivity of the patients such as an undifferentiated carcinoma of the tongue base, [47] a pleomorphic adenoma of the nasal septum. [48] It is well known that some inflamatory, lymphoid disorders and lymphomas, such as Burkitt's lymphoma, are related to EBV. [18],[19],[49],[50],[51],[52] Recently, occasional types of salivary gland carcinomas have also been reported with EBV positivities. [53],[54]

However, some authors claim that EBV might have a role in the pathogenesis in laryngeal supporting a definitive association (SCC). However, there are no studies supporting an association with EBV. [55],[56],[57],[58],[59],[60],[61] In our study, seven control cases of laryngeal conventional SCC were immunohistochemically negative for EBV LMP-1 and EBV EBNA-2.

Till date, there has been no study focusing on the SC of the upper aerodigestive tract with EBV association by IHC . In the current study, while four cases showed EBV LMP-1 positivity (50%), there was no EBV EBNA-2 positivity seen. However, the EBV LMP-1 results of our series could be considered only as a coincidental finding in the SCs of the upper aerodigestive tract. This finding supports the idea that further studies based on larger series might be helpful to enlighten the role played by EBV in carcinogenesis of SC.

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